Promoter SNPs Alter CCR5 Expression and HIV Propagation

Case Western Reserve University, Cleveland OH

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Abstract

Description (provided by applicants): The hypothesis to be tested is that CCR5 gene polymorphism influences receptor expression and cellular propagation of HIV infection, and will influence the efficacy of topical agents, such as PSCRANTES, applied to block R5 viral strain infection in vitro and in vivo. Our recent studies suggest that CCR5 promoter polymorphism at the single nucleotide polymorphism (snp), A-2459G is associated with heterogeneous receptor expression and viral propagation. We observed that the density of CCR5 on CD4+ monocytes, and propagation of R5 HIV(JR-FL) in PBMCs and human Langerhans cells as significantly lower on cells from individuals with the - 2459 G/G, compared to A/G and A/A genotypes (for each analysis P<0.05, Kruskal-Wallis test). These findings suggest that CCR5 polymorphisms, common in most human ethnicities, may influence the success of strategies to block HIV infection by down-modulating CCR5 expression. In anticipation that chemokine analogues may be tested in trials for protection against mucosal HIV transmission, understanding relationships between host genetic polymorphisms and responsiveness to these analogues is important, particularly in the developing world as a better understanding of the prevalence of key CCR5 polymorphisms in these populations is needed. Specific aims of this proposal are: (1) To determine the distribution of CCR5 polymorphisms in Ugandan subjects; (2) To examine the relationships between these polymorphisms and CCR5 expression on phenotypically defined CD4+ cell subsets and LC from epithelial tissue explants; (3) To examine the relationships between these polymorphisms CCR5 density and the ability of cells to support propagation of R5 viruses in vitro; and (4) To determine if these polymorphisms affect the ability of amino terminal modification to RANTES analogues to down-modulate cell surface-level expression of CCR5 and/or block infection by R5 viruses in vitro.